C-Terminal Tetrapeptides Inhibit A尾42-Induced Neurotoxicity Primarily through Specific Interaction at the N-Terminus of A尾42

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• 作者：Huiyuan Li ; Zhenming Du ; Dahabada H. J. Lopes ; Erica A. Fradinger ; Chunyu Wang ; Gal Bitan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8451-8460
• 全文大小：418K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

Inhibition of amyloid 尾-protein (A尾)-induced toxicity is a promising therapeutic strategy for Alzheimer鈥檚 disease (AD). Previously, we reported that the C-terminal tetrapeptide A尾(39鈥?2) is a potent inhibitor of neurotoxicity caused by A尾42, the form of A尾 most closely associated with AD. Here, initial structure鈥揳ctivity relationship studies identified key structural requirements, including chirality, side-chain structure, and a free N-terminus, which control A尾(39鈥?2) inhibitory activity. To elucidate the binding site(s) of A尾(39鈥?2) on A尾42, we used intrinsic tyrosine (Y) fluorescence and solution-state NMR. The data suggest that A尾(39鈥?2) binds at several sites, of which the predominant one is located in the N-terminus of A尾42, in agreement with recent modeling predictions. Thus, despite the small size of A尾(39鈥?2) and the hydrophobic, aliphatic nature of all four side-chains, the interaction of A尾(39鈥?2) with A尾42 is controlled by specific intermolecular contacts requiring a combination of hydrophobic and electrostatic interactions and a particular stereochemistry.